Neurodegenerative eye diseases such as glaucoma cause blindness in a large population in the USA, yet effective treatments are lacking. The ultimate goal of this project is to develop new methods for rescue of retinal neurodegeneration by exploiting a unique endogenous neuroprotective agent, the ?1R chaperone, whose anti-apoptotic properties are being uncovered. Our in vivo studies suggest that the ?1R is ROS (reactive oxygen species)-suppressing and is protective against retinal degeneration in ganglion cells as well as in photoreceptors. This project represents the first study to test the efficacy of the ?1R-mediated retinal neuroprotection by ?1R gene therapy, by overexpressing the ?1R in stem cell-derived photoreceptors to enhance their post-transplantation survival, and by using the sigma-1 receptor knock model (?1ko) combined with the chronic DBA/2J glaucoma model or rd10 model. In Specific Aim 1, we will examine the impact of the absence of the ?1R for the viability of ganglion cells and photoreceptors in vivo in the DBA/2J model of glaucoma and the rd10 model of RP, respectively. Since we have discovered that ganglion cells of the ?1ko mice are more susceptible to retinal degeneration than the wild type in an acute model, we will further test our finding using a new model crossed with the ?1ko and the chronic glaucoma model of DBA/2J. We will also extend our investigation into a neuroprotective role of the ?1R in retinal photoreceptors, which has yet to be defined, in a new model that we have generated by crossing ?1ko and rd10. Retinal ROS levels will be compared in the presence and absence of the ?1R in these models. In Specific Aim 2, we will test ?1R gene therapy for rescue of retinal degeneration using lentiviruses. To increase the ?1R abundance in the retina, we will transduce the rd10 mouse photoreceptors with lentiviruses harboring the ?1R gene and the Opsin promoter using a technique of subretinal injection. Retinal functions of the transgenic eye overexpressing the ?1R will be compared to that injected with the ?1R-negative mock virus. In Specific Aim 3, we will explore the neuroprotective effect of the ?1R on the post-transplantation survival of stem cell-derived photoreceptors. In stem cell therapy, elevated oxidative stress due to the death of rods, which are active major consumers of oxygen in the retina, imposes detrimental threat to the survival of transplanted photoreceptors. We will overexpress the ?1R in human embryonic stem cell-derived photoreceptors to enhance their survival after transplantation into the rd10 retina. The pro-survival effect of the ?1R on transplanted photoreceptors will be assessed in comparison to the control transplant cells that are transduced with the ?1R-negative mock virus. Ultimately, our finding will lead to new ?1R-targeted therapeutic strategies for rescue of the devastating retinal neurodegenerative diseases.